Background
The Leeds Team has been at the forefront of the biology of psoriasis and psoriatic arthritis [1]. Interleukin (IL)-23 is a pivotal cytokine in the pathogenesis of both diseases [2]. The IL-23/IL-17 cytokine axis regulation in psoriasis and arthritis in vivo is still poorly understood but the pathway is also inextricably linked to fungal immunity, with fungal cell wall glycan biology being crucial to activating the innate immune responses.
We hypothesise that binding of fungal surface glycans with dendritic cells (DCs) will induce specific clustering (depending on the glycan affinity and pattern) of the DC surface glycan receptor, DC-SIGN, as a way to activate its cross-talking properties, which in turn regulates the intracellular signalling pathways for IL-23 production.
The project will develop glycosylated gold nanoparticles as a mimic of the fungal surface glycan structures to investigate the mechanisms of fungal mediated activation of IL-23, and to develop potential anti-fungal therapeutics.
Aims and objectives
- To synthesise mannose and oligomannose glycans to mimic fungal surface glycan structures;
- To prepare glycosylated gold nanoparticles (glycan-GNPs) of varied size (e.g. 5, 13, 25, 50, 100nm), shape (spherical or rod shape) and glycan density to mimic fungal surface glycan patterns, and to study their binding affinity and specificity with DC-SIGN molecules via fluorescence quenching assays [3,4];
- To investigate how binding of fungi surface glycans mimicking glycan-GNPs with DC induces DC-SIGN clustering and modulate IL-23/IL-17 expression and alters the immune profile of dendritic cells, by transcriptional profiling;
- To investigate how DC-SIGN cross talk with other pattern recognition receptors to regulate this process and how this response can be controlled by glycan-GNPs for potential anti-fungal therapeutic development.
Research Methodologies
The multidisciplinary project cuts across the Schools of Chemistry, Food Science and Nutrition, and the Leeds Institute of Rheumatic & Musculoskeletal Medicine (LIRMM) at the University of Leeds. It will involve the synthesis of specific carbohydrates and linker molecules; conjugation them onto nanoparticles to make fungal surface glycan mimicking glycan-GNPs; study their binding affinity with DC-SIGN molecules via our established fluorescence assays [3,4]; and study how their binding affects DC surface DC-SIGN clustering, IL-23/IL-17 expression and cross-talking properties. Training in cell biology (e.g., cell culture, immunoassays) will be provided.
Applicants should have a keen interest in applying the synthetic and nanochemistry methods to address biological questions and enjoy working in a highly dynamic and collaborative environment.
Self-motivation, good communication and interpersonal skills are essential.
Training will be provided in the following areas
- Organic and nanoparticle synthesis,
- Cell Biology techniques, including cell culture, flow cytometry and ELISA
Environment:
The student will be based in the University of Leeds between the Schools of Chemistry, Food Science and Nutrition. and Medicine The cell biology and immunoassays work will be done in the Leeds Institute of Rheumatic and Musculoskeletal Medicine based at the Wellcome Trust Brenner Building at the St. James’s University Hospital site.
Eligibility
You should hold a first degree equivalent to at least a UK upper second class honours degree in Chemistry. This project would suit a student with a strong background in organic chemistry or nanochemistry.
Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests are: • British Council IELTS - score of 6.5 overall, with no element less than 6.0 • TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.
How to apply
We strongly encourage applicant to contact the supervisor(s) for informal discussion about the suitability of the project before applying to the University: Prof Dennis McGonagle ([Email Address Removed]), Prof Dejian Zhou ([Email Address Removed]) or Dr Yuan Guo ([Email Address Removed])
Applicants should complete an online application form and attach the following documentation to support their application.
- a full academic CV
- degree certificate and transcripts of marks
- Evidence that you meet the University's minimum English language requirements (if applicable).
To help us identify that you are applying for this scholarship project please ensure you provide the following information on your application form;
- Select PhD in Medicine as your programme of study
- Give the full project title and name the supervisors listed in this advert
- For source of funding please state you are applying for a Bristol Myers Squibb funded scholarship
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